The contents of all cited references are expressly incorporated by reference. Tourette's Disorder (TD), thought to be a lifelong condition, is a childhood onset neuropsychiatric disorder characterized by multiple motor and vocal tics that is associated with considerable disability and reduction in quality of life (DSM IV-TR, 2000). The majority of clinically referred youth with TD also meet criteria for comorbid Obsessive-Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD), and young adults meet criteria for additional anxiety, mood and substance use disorders. (Coffey B, Biederman J, Spencer T et al 2000; Coffey, Miguel, Biederman, JNMD 1998). Research in the past decade suggests peak tic severity occurs at about age 10-11 years with improvement into adolescence, and gradual attenuation of tics by early adulthood. However, a substantial minority of individuals with TD continue to experience disabling tic symptoms throughout their lives.
Common motor tics include, but are not limited to: eye blinking, coughing, throat clearing, sniffing, and facial movements. Simple vocal tics include involuntary inarticulate noises while complex vocal tics include syllables, words, phrases and in extreme cases includes derogatory remarks and profanity (coprolalia). The disorder often accompanies other disorders such as attention deficit hyperactivity disorder and obsessive compulsive disorder.
Tourette's Disorder is known to have genetic and environmental causes although the exact mode of inheritance is unknown. Diagnosis under the DSM-IV includes the presence of multiple motor tics and at least once vocal tic for greater than one year; onset prior to age 18; and frequent tics which cause distress or impairment which are not secondary to another condition.
A discussion of current therapies for treatment of Tourette's disorder can be found in Lyon, Gholson G, et al. Tourette's Disorder, Current Treatment Options in Neurology, 12: 274-286 (2010). Treatment of Tourette's Disorder includes administration of the antihypertensive alpha-2-agonists clonidine and guanfacine, administration of atypical neuroleptics such as olanzapine, ziprasidone, and risperidone; classic neuroleptics such as haloperidol, pimozide; tetrabenzanine; agents which deplete presynaptic dopamine and serotonin stores and which block postsynaptic dopamine receptors such as tetrabenazine. Benzodiazapines also appear in the literature but have not been subject to controlled clinical trials. Motor tics have also been treated with botulinum toxin.
Emerging therapies currently undergoing studies include levetiracetam, topiramate, the GABA-B agonist baclofen, and the dopamine agonists pergolide, cabergoline, ropinirole and pramipexole.
Clonidine and guanfacine, while having limited long term side effects limited largely to sedation, fatigue and somnolence, are only about 30% to 35% effective at reducing symptoms. The neuroleptic antipsychotics have a variable risk of extrapyramidal side effects that include akathisia, tardive dyskinesia and dystonias as well as affective constriction and cognitive blunting. The only formally approved treatments for TD are haloperidol and pimozide, which are typical neuroleptic agents known to have these adverse effects (Scahill et al 2006). Given the significant potential for adverse effects associated with use of typical neuroleptics, better tolerated and efficacious alternatives are needed.
Tics are thought to result from disinhibition of the cortico-striatal-thalamo-cortical tracts, pathways involved in habit formation, linking the basal ganglia, thalamus and frontal cortex. (Leckman et al JCAP, 2010). Multiple converging lines of evidence, including clinical trials with D2 dopamine receptor antagonists and in vivo neuroimaging studies of DAT binding in the striatum, suggest that TD is a disorder of dopaminergic transmission, conceptualized as an excess of nigrostriatal dopamine activity through dysfunctional presynaptic receptors or hyperfunctional dopamine innervation. More recent evidence has suggested that other neurotransmitters, specifically GABA, may also play a significant role in the pathophysiology of TD, particularly with regard to GABAergic neurons' impact on dopaminergic pathways. GABA neurons are present in the “direct pathway” of medium spiny neurons projecting to the internal segment of the globus pallidus and substantia nigra, and in the “indirect pathway” from the striatum to the external segment of the globus pallidus and on to the internal segment (Leckman et al JCAP 2010). Several postmortem studies of TD patients identified marked decreased in number and density of GABA-ergic parvalbumin-positive neurons in the basal ganglia, for example, more than 50% reduction in FSINs in caudate and 30-40% reduction in putamen. (Kalanithi et al., 2005; Kataoka et al., 2010). Another study reported more than 50% reduction of GABAergic Fast spiking GABAergic interneurons (“FSINs”) and loss of TANs (tonically active neurons). In addition, preliminary findings from a Tourette Syndrome Association sponsored study of GABA brain concentrations in adolescents with TD indicate significantly decreased anterior cingulated cortex (ACC) and striatal GABA in adolescents with TD relative to healthy controls (Gabbay and Coffey, 2011).
FSINs and cholinergic tonically active neurons (TANs) are thought to play an important role in modulation of tics and habit learning. FSINs are reported to show characteristic irregular bursting with stable intra-burst frequencies similar to tic patterns (Peterson and Leckman, 1998) TANs are reported to be sensitive to salient perceptual signals and respond to dopaminergic input from the substantia nigra.
To the extent that tics are a likely manifestation of phasic dopamine (DA) activity, clinical experience with other conditions characterized by such properties, e.g. cocaine and methamphetamine addiction would suggest that vigabatrin may be effective in reducing tics. Vigabatrin, at doses that are FDA approved for treatment of epilepsy is well tolerated and should be well tolerated for the treatment of Tourette's Disorder.
Vigabatrin (γ-vinyl GABA) has not previously been used for treatment of Tourettes Disorder but it has been used for treatment of neurological disorders. Vigabatrin is sold worldwide under the trademark Sabril™ for treatment of epilepsy. Vigabatrin has been studied for treatment of drug addiction. Vigabatrin's well known mechanism of action is the irreversible inhibition of gamma-aminobutyric acid-aminotransferase (GABA-AT). This enzyme is responsible for the catabolism of gamma aminobutyric acid (GABA) in the brain. Inhibition of this enzyme results in an elevation of brain levels of GABA. The elevation of brain GABA (the brain's primary inhibitory neurotransmitter) results in a decrease of neuron excitability and as such reduces uncontrolled firing of neurons, which leads to a reduction in epileptic seizures.
U.S. Pat. Nos. 7,381,748 and 6,794,413, which are incorporated herein by reference disclose the compound (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid. The literature has shown that (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid is approximately 52 times more potent as a mechanism-based inactivator of γ-aminobutyric acid aminotransferase (GABA-AT) than the anticonvulsant drug and GABA-AT inactivator vigabatrin (Sabril™) under nonoptimal conditions (conditions other than physiological pH and temperature) (Pan, Y.; Qiu, J.; Silverman, R. B. Design, Synthesis, and Biological Activity of a Difluoro-substituted, Conformationally-rigid Vigabatrin Analogue As a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor. J. Med. Chem. 2003, 46, 5292-5293).
The phrase “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds of the invention that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in vigabatrin or (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid. Suitable acids include: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid. can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see Berge et al., 66 J. Pharm Sci 1-19 (1977) and P. Heinrich Stahl, Camille G. Wermuth (Eds.) Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley, (2002), the contents of which are expressly incorporated herein by reference.
U.S. Pat. Nos. 6,906,099; 6,890,951; 6,828,349; 6,593,367; 6,541,520; 6,395,783; 6,323,239; and 6,057,368 which describe and/or claim the use of vigabatrin in the treatment of addiction from cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxymethamphetamine, and/or PCP, the contents of such patents are expressly incorporated herein by reference.
U.S. Pat. No. 6,462,084 describes and/or claims the use of vigabatrin in the treatment of obsessive compulsive disorders including general anxiety disorder, pathological or compulsive gambling disorder, compulsive eating (obesity), body dysmorphic disorder, hypochondriasis, pathologic grooming conditions, kleptomania, pyromania, attention deficit hyperactivity disorder and impulse control disorders. The contents of U.S. Pat. No. 6,462,084 is expressly incorporated herein by reference.
U.S. Pat. No. 6,939,876 describes and/or claims the use of vigabatrin in the treatment to prevent addiction to opioid analgesics by co administration of vigabatrin. The contents of U.S. Pat. No. 6,939,876 is expressly incorporated herein by reference.
GABA-ergic drugs are those which improve synaptic concentration or activity of GABA or increase the activation of GABA receptors, directly or indirectly. These drugs as a family have been used to treat a wide variety of nervous system disorders including fibromyalgia, neuropathy, migraines related to epilepsy, restless leg syndrome, and post traumatic distress disorder, anxiety, and insomnia. GABA-ergic drugs include GABAA and GABAB receptor ligands, GABA reuptake inhibitors, GABA aminotransferase inactivators and inhibitors, GABA analogs, or molecules containing GABA itself. Currently marketed GABA-ergic drugs that could possibly be useful for the treatment of Tourette's Disorder include valproate and its derivatives, vigabatrin, pregabalin, gabapentin and tiagabine.
Once GABA-AT (GABA-aminotransferase) has been inactivated, it takes a number of days for the brain to synthesize new GABA-AT to replace the inactivated enzyme. Researchers have demonstrated (Petroff, Ognen A. C.; Rothman, Douglas L.; “Measuring Human Brain GABA In Vivo, Effects of GABA-Transaminase Inhibition with Vigabatrin”, Molecular Neurobiology, 1998, 16(1), 97-121) that brain GABA levels remain substantially elevated for several days after administration of a single dose of vigabatrin. This observation is consistent with the assertion that it takes several days for the brain to restore the GABA-AT activity.
It is an object of the present invention to treat Tourette's Disorder by delivering a GABA aminotransferase inactivator to a patient in need thereof.
It is an object of this invention to treat patients having Tourette's Disorder using an irreversible inactivator of GABA aminotransferase.
It is an object of this invention to use Vigabatrin and its derivatives to treat Tourette's Disorder.
It is an object of the present invention to treat Tourette's Disorder using (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid and its pharmaceutically acceptable salts.